Project Summary Malaria affects almost one-half of the world's population and causes more than 500,000 deaths annually. Young children in malaria endemic areas of Africa have the highest mortality rate because of their immature immune systems. Global efforts to control the disease have had limited success, and no vaccine has yet been approved for clinical use. Therefore, there is an urgent, unmet need to discover new vaccine candidates. A vaccine against childhood malaria is a priority because children below the age of 5 years are highly vulnerable to the disease. In recent studies, our laboratory discovered Schizont Egress Antigen-1 (PfSEA-1), a 244-kDa- parasite antigen that is crucial for parasite egress from an infected red blood cell (iRBC), which was published as a comprehensive, full-length Research Article in Science. In a parallel approach, we have screened a phage display cDNA library constructed from parasites isolated at our Tanzanian field site using positive selection with antibodies pooled from resistant two-year-olds and negative selection with antibodies pooled from susceptible children. We identified several independent cDNA clones encoding plant-like calcium-dependent protein kinase (PfCDPK5) that were uniquely recognized by antibodies in resistant, but not susceptible sera. Our preliminary data demonstrate that PfCDPK5 is critical for parasite egress and is expressed by merozoites as they rupture from erythrocytes. Antibodies against CDPK5 block parasite growth in vitro, protect mice from parasitemia, and extend the survival of mice challenged with lethal P. berghei ANKA. Furthermore, PfCDPK5 interacts with other proteins (PfSEA) involved in parasite egress. The proposed work will evaluate the association between naturally acquired anti-PfCDPK5 antibody responses and protection from malaria infection and disease. We will also evaluate the in vivo efficacy of vaccination with rPbCDPK5 in mice and conduct initial optimization studies of adjuvant-antigen formulation using both soluble and particulate forms of the antigen. These studies will form the core supporting data for follow-on vaccine trials in non-human primates with the ultimate goal of a malaria vaccine for humans.